Cerebellar volume correlates with saccadic gain and ataxia in adult Niemann-Pick type C

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Abstract

Background and purpose

Cerebellar Purkinje cells are known to be highly vulnerable to neuronal pathology in Niemann-Pick type C (NPC), a disease where widespread white matter changes have also been reported. We sought to determine the relationship between white and grey matter cerebellar changes and clinical variables in NPC.

Materials and methods

Ten adult patients with NPC were matched to control subjects (n = 27) on age and gender. Patients were rated for symptom duration and severity, degree of ataxia, and were assessed for saccadic eye measures. Cerebellar white and grey matter volumes were automatically segmented using the Freesurfer software package.

Results

NPC patients had a significant reduction in both grey and white matter volumes. Volume did not correlate with symptom duration or severity, but did correlate with saccadic gain and ataxia measures.

Conclusions

Both cerebellar grey and white matter volume decreases in adult NPC, and these changes are associated with impairments in saccadic gain and in motor control.

Highlights

► Cerebellar volume loss in adult Niemann-Pick type C is driven by changes to both white and grey matter. ► Reduced cerebellar volume correlates with ataxia measured on the Brief Ataxia Rating Scale. ► Reduced saccadic gain may be driven by cerebellar and brainstem changes.

Introduction

Niemann-Pick disease type C (NPC) is an autosomal recessive progressive neurovisceral disorder that presents in both children and adults. Cellular changes in NPC result from alterations to intracellular sterol cycling, as a result of mutations to the genes encoding for the large transmembrane endosomal NPC1 and smaller soluble lysosomal NPC2 proteins. In adults, it presents with ataxia, vertical gaze palsy, cognitive impairment and splenomegaly [1], [2], with a number of adults also presenting with major neuropsychiatric illness such as schizophrenia-like psychosis or bipolar disorder [3], [4].

As a result of impairment to the function of NPC1/2, unesterified cholesterol and glycosphingolipids accumulate in lysosomes and late endosomes [1], which in the CNS results in altered dendritic and axonal morphology [5], alter axonal transport and intracellular lysosomal transport, impair intracellular calcium homeostasis [6], the accumulation of hyperphosphorylated tau [7], and affect neuronal-glial interactions [8]. The Purkinje cells in the cerebellum appear to be a particularly sensitive neuronal population to these changes, with both feline and murine models demonstrating widespread and early changes. In NPC mouse models, intracellular storage of GM2 and GM3 gangliosides is particularly conspicuous in Purkinje cells [9], [10], [11], and neuronal loss occurs in a stepwise fashion, with neurons in lobules IX and X in the posterior vermis surviving longest [12]. Purkinje cell loss is likely the result of autonomous degeneration via autophagy [13], [14], which is likely driven by both the TNF-alpha death pathway and apoptotic cell loss [15]. In the NPC cat model, whilst abnormal storage products occur in neurons across the CNS, only cerebellar Purkinje neurons are completely lost [16], with these cell populations exhibiting the high levels of GM2 excess, ectopic dendritic sprouting [17] and axonal spheroid formation [18].

In limited human neuropathology work, age-related Purkinje cell loss has been described, in addition to abnormalities in axonal and neuronal ultrastructure, lipid accumulation in dendrites, and cytoplasmic inclusions [19]. Although the cerebellum accumulates hyper-phosphorylated tau, unlike in other brain regions in NPC, there appears to be no formation of neurofibrillary tangles, perhaps because of the relative paucity of tau in this brain region [19].

Magnetic resonance imaging (MRI) is a non-invasive way to probe the integrity of a variety of brain regions including the cerebellum. Abnormalities in cerebellar structure have been reported as abnormal in single patients and small series, with findings including volume loss [20], [21], and reduced magnetisation transfer ratio [22]. We have previously shown, using a voxel-based approach, that cerebellar volume loss (particularly in anteromedial regions) is demonstrable on MRI scanning in adult NPC sufferers, and accompanies significant subcortical volume loss in regions such as the thalamus, striatum and hippocampus [23]. This analysis did however demonstrate that white matter changes were widespread in adult NPC patients, whereas grey matter changes were relatively restricted to a number of discrete subcortical structures. What is not known is how structural changes in the cerebellum relate to clinical, neurological and biochemical variables of the disorder, and the relative contribution of grey and white matter changes to these variables. In this study we aimed to robustly quantify cerebellar white and grey matter volumes, and to correlate these with a range of illness-related variables.

Section snippets

Subjects

Data was acquired from 10 adult NPC patients (6 male, 4 female), all from the Royal Melbourne Hospital, Australia (Table 1), between 2000 and 2010. All adult NPC patients assessed during this period were included. Diagnosis was confirmed with biochemical analysis of cultured fibroblasts, using cholesterol esterification rate and percentage of cells staining abnormally for perinuclear cholesterol for nine patients, with one patient confirmed genetically only. Duration of symptoms were acquired,

Demographic data

Demographic data is presented in Table 1. There were no significant differences between the control and NPC groups in age (t = 0.351, p = 0.730) or gender (χ2 = 0.027, p = 0.869).

Cerebellar volume

Results from cerebellar volume estimation are presented in Table 2 and Fig. 2. When controlling for intracranial volume, there was a significant reduction in TCV (F = 11.34, p = 0.002), and its component TCGM (F = 10.06, p = 0.003) and TCWM (F = 8.56, p = 0.006). Multivariate analysis examining the role of laterality in TCV showed no

Discussion

We have demonstrated that there are significant differences in both white and grey matter cerebellar volume in adult NPC patients compared to matched controls, and that the combined reduction in these tissue classes results in a reduction in total cerebellar volume. These changes do not appear to relate to duration of illness or total illness scale score, but do correlate to ataxia measures and brainstem measures of ocular-motor function.

That these clear between-group changes do not clearly

Conclusion

Our results suggest that both cerebellar grey and white matter volume change occur in adults with NPC, and may be an early feature of the illness. Longitudinal studies in adult patients from an early illness stage would confirm whether cerebellar volume reductions are an early feature, and whether this may be a putative early diagnostic marker for adult patients with features suggestive of NPC.

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